Migraine is a common neurovascular disorder, typically characterized by recurring disabling attacks of headache and associated autonomic symptoms (migraine without aura);in up to one third of patients attacks are associated with additional neurological aura symptoms (migraine with aura). The attack frequency ranges from a few in a lifetime to several per week (median: 1.5 attacks/month). Evidence is accumulating that migraine attacks might also permanently affect the brain. Clinic-based studies (i.e. primarily including severely affected patients) suggest that migraine is an independent risk factor for clinical stroke, magnetic resonance imaging (MRI)-visible cerebral white matter lesions (WML), mild cognitive impairment, and cerebellar dysfunction. Our group showed in the cross-sectional population-based CAMERA MRI study, that migraine cases from the general population are at increased risk of WML and cerebellar infarct-like lesions. Most importantly, the risk increased with increasing attack frequency, in particular in females and migraineurs with aura. This would suggest that recurrent migraine attacks might indeed progressively affect the brain in subgroups of patients. Such a relationship, however, needs to be demonstrated in a longitudinal design. We propose to rescan and re-evaluate the entire CAMERA case and control sample (n=435) that was originally scanned in 1999 and 2000. This unique 8-9 year follow-up study of brain MRI and clinical characteristics will be based on a sample of 295 migraine cases and 140 non-migraine controls from the general population. In addition, because of the limited number of cases with >2 attacks/month in the CAMERA study, we will include a second study population with patients (n=150) suffering from >2 migraine with aura attacks/month. Because of the high prevalence of patent foramen ovale (PFO) in migraine with aura, inclusion of these patients would also allow for a better assessment of the contribution of PFO to migraine- related brain lesions. In the CAMERA population we will assess onset and progression of brain lesions and correlate these findings with gender, migraine characteristics (aura, attack frequency, use of migraine medication) and presence of PFO. In addition, we will evaluate the presence of cognitive impairment and cerebellar dysfunction, and correlate these findings with the MRI findings. In the second study population we will assess the effect on MRI brain lesion load of a very high number of attacks with aura and the contribution of the presence of PFO. The ultimate goal of our study is to answer the important healthcare question whether recurring migraine attacks may cause functionally relevant brain lesions which could potentially be prevented by a more aggressive preventative treatment of migraine. Relevance Migraine is a highly prevalent brain disorder, clinically primarily characterized by attacks of headache and associated symptoms which are believed to be harmless to the brain. Triggered by preliminary evidence, we propose to assess whether recurring migraine attacks might permanently and progressively affect the brain, and whether this relates to brain dysfunction. If confirmed, this would call for an earlier and more aggressive prophylactic treatment of migraine to prevent attacks and related brain damage.